U.S. patent number 5,169,942 [Application Number 07/795,575] was granted by the patent office on 1992-12-08 for method for making 2-(18f)fluoro-2-deoxy-d-glucose.
This patent grant is currently assigned to General Electric Company. Invention is credited to Bruce F. Johnson, Donald H. Maylotte, Cheryl L. Sabourin.
United States Patent |
5,169,942 |
Johnson , et al. |
December 8, 1992 |
Method for making 2-(18F)fluoro-2-deoxy-D-glucose
Abstract
A method is provided for making 2-[.sup.18 F]fluoro-2-
deoxy-D-glucose which employs a phase-transfer reagent, consisting
of a tetraalkylammonium bicarbonate, a tetraalkylammonium
carbonate, or a mixture of a tetraalkylammonium hydroxide and
potassium bicarbonate.
Inventors: |
Johnson; Bruce F. (Scotia,
NY), Maylotte; Donald H. (Schenectady, NY), Sabourin;
Cheryl L. (Albany, NY) |
Assignee: |
General Electric Company
(Schenectady, NY)
|
Family
ID: |
25165877 |
Appl.
No.: |
07/795,575 |
Filed: |
November 21, 1991 |
Current U.S.
Class: |
536/122; 536/124;
536/18.4; 536/18.5 |
Current CPC
Class: |
C07H
5/02 (20130101) |
Current International
Class: |
C07H
5/00 (20060101); C07H 5/02 (20060101); C07H
001/00 (); C08B 037/00 () |
Field of
Search: |
;536/122,124,18.4,18.5 |
Primary Examiner: Griffin; Ronald W.
Attorney, Agent or Firm: Teoli; William A. Pittman; William
H.
Claims
What is claimed is:
1. A method for making [.sup.18 F]fluoro-2-deoxy-D-glucose which
comprises,
(1) contacting at a temperature of 40.degree. C. to 100.degree. C.,
1,3,4,6-tetra-O-acetyl-2-0-trifluoromethanesulfonyl-2-deoxy-.beta.-D-manno
pyranose and [.sup.18 F]fluoride ion in the presence of a 60 to 95
volume % organic solvent solution of a phase-transfer reagent
selected from the class consisting of a tetraalkylammonium
bicarbonate, a tetraalkylammonium carbonate and a mixture of a
tetraalkylammonium hydroxide and potassium bicarbonate, and
(2) effecting the substantial removal of the organic solvent,
and
(3) heating the resulting mixture of (2) in the presence of an
aqueous hydrogen halide until deprotection of the resulting
acetylated 2-[.sup.18 F]fluoro-2-deoxy-D-glucose is effected,
where the organic solvent of (2) is a member selected from the
class consisting of acetonitrile and propionitrile.
2. A method in accordance with claim 1, where the phase-transfer
reagent is tetraethylammonium bicarbonate.
3. A method in accordance with claim 1, where the phase-transfer
reagent is tetrabutylammonium bicarbonate.
4. A method in accordance with claim 1, where the phase-transfer
reagent is tetrahexylammonium bicarbonate.
5. A method in accordance with claim 1, where the phase-transfer
reagent is a mixture of tetraalkylammonium hydroxide and potassium
bicarbonate.
6. A method in accordance with claim 1, where the organic solvent
is acetonitrile.
Description
BACKGROUND OF THE INVENTION
The present invention relates to a method for synthesizing
2-fluoro-2-deoxy-D-glucose with an [.sup.18 F]fluoride ion prepared
without addition of a carrier to produce a radiopharmaceutical for
Positron Emission Tomography (PET). More particularly, the present
invention relates to a method for making
2-[;8F]fluoro-2-deoxy-D-glucose involving the replacement of the
trifluoromethanesulfonyl group (triflate) with an [.sup.18
F]fluoride ion, in
1,3,4,6-tetra-O-acetyl-2-triflate-.beta.-D-mannopyranose, where a
phase-transfer catalyst is used in the form of a tetraalkylammonium
bicarbonate, or a mixture of a tetraalkylammonium hydroxide and an
alkali bicarbonate. Prior to the present invention, various
procedures were used for making 2-[.sup.18
F]fluoro-2-deoxy-D-glucose or "[.sup.18 F]2FDG", which is the most
widely used radiopharmaceutical ositron Emission Tomography (PET).
Considerable effort has been expended in the development and
refinement of such procedures. Because of its decay energy, (0.64
MEV) the [.sup.18 F]fluoride ion allows the highest inherent
resolution during PET measurements and has a relatively convenient
half life of 109.7 min. The following equation illustrates the
preferred procedure for making [.sup.18 F]2FDG: ##STR1## where Ac
is acetate, and PTR is phase-transfer reagent.
One methOd of synthesizing [.sup.18 F]2FDG by the above procedure
is shown by Hamacher et al., Journal of Nuclear Medicine,
27:235-238, (1986). Hamacher et al. employ an aminopolyether
[Kryptofix 222 or K222]-potassium carbonate complex as a
phase-transfer catalyst for [.sup.18 F]fluoride. An additional
procedure for making [.sup.18 F]2FDG is shown by Brodack et al.,
Applied Radiation and Isotope, Volume 39, No. 7, pages 699-703
(1988) involving the employment of a tetrabutylammonium hydroxide
as a phase-transfer catalyst in place of the aminopolyether
potassium complex of Hamacher et al. Although Brodack et al.
disclose that the triflate reacts with [.sup.18 F]fluoride ion
using the tetrabutylammonium counter ion, a yield of 12-17% is
reported which is significantly below the level considered
acceptable for commercial robotic production of [.sup.18
F]2FDG.
SUMMARY OF THE INVENTION
The present invention is based on a discovery that significantly
improved yields of [.sup.18 F]2FDG can be obtained using the above
shown synthesis, by substituting for tetraalkylammonium hydroxide
as the phase-transfer reagent, a mixture of substantially equal
molar amounts of tetraalkylammonium hydroxide and potassium
bicarbonate. In addition, further improvements in [.sup.18 F]2FDG
yields can be realized if tetraalkylammonium bicarbonates, such as
tetraethylammonium bicarbonate or tetrabutylammonium bicarbonate
are used directly as the phase-transfer reagents.
STATEMENT OF THE INVENTION
There is provided by the present invention, a method for making
2-[.sup.18 F]fluoro-2-deoxy-D-glucose which comprises,
(1) contacting
1,3,4,6-tetra-O-acetyl-2-0-trifluoromethanesulfonyl-2-deoxy-.beta.-D-manno
pyranose and [.sup.18 F]fluoride ion in the presence of an inert
organic solvent at a temperature of 40.degree. C. to 100.degree. C.
and a phase-transfer reagent selected from the class consisting of
a tetraalkylammonium bicarbonate, a tetraalkylammonium carbonate
and a mixture of a tetraalkylammonium hydroxide and alkali metal
bicarbonate, and
(2) effecting the substantial removal of the organic solvent,
and
(3) heating the resulting mixture of (2) in the presence of an
aqueous hydrogen halide until deprotection of the resulting
acetylated 2-[.sup.18 F]fluoro-2-deoxy-D-glucose is effected.
The term tetraalkylammonium bicarbonate or "TAAHCO.sub.3 " will
mean, hereinafter, specific compounds such as tetraethylammonium
bicarbonate, tetrabutylammonium or tetrahexylammonium bicarbonate,
or a mixture of substantially equal molar amounts of
tetraalkylammonium hydroxide and alkali metal bicarbonate such as
potassium bicarbonate. In forming the TAAHCO.sub.3 phase-transfer
reagent by combining KHCO.sub.3 and tetraalkylammonium hydroxide,
the KHCO.sub.3 can be added to a mixture of tetraalkylammonium
hydroxide and an organic solvent, such as acetonitrile and [.sup.18
F]fluoride ion in water enriched with H.sub.2.sup.18 O, resulting
from the bombardment of the H.sub.2.sup.18 O with high energy
protons or in sterile water added after removal of the enriched
water. In instances where tetraalkylammonium bicarbonate is used
directly as the phase-transfer reagent, it can be prepared by the
following procedure:
CO.sub.2 is bubbled through an aqueous solution of
tetraalkylammonium hydroxide (5.sub.]25 weight%, pH>12) until
the pH has stabilized at 7-8. The flask can be evacuated to remove
excess CO.sub.2, concentrated to remove water and taken up in
CH.sub.3 CN. The concentration of the tetraalkylammonium
bicarbonate can be confirmed by treating a known volume of the
solution with excess acetic acid and measuring the volume of
CO.sub.2 released.
If desired tetraalkylammonium carbonate also can be used as a
phase-transfer catalyst which can be formed as follows:
CO.sub.2 is bubbled through an aqueous solution of a known volume
of tetraalkylammonium hydroxide (5-25 weight%, pH>12) until the
pH has stabilized at 7-8. The flask is evacuated to remove CO.sub.2
and then the same volume of tetraalkylammonium hydroxide is added.
The solution can be concentrated and taken up in CH.sub.3 CN. The
concentration of the tetra-alkylammonium carbonate can be confirmed
by treating a known volume of the solution with excess acetic acid
and measuring the volume of CO.sub.2 released.
In the practice of the preferred form of the invention, the
TAAHCO.sub.3, as an organic solvent solution, can be added along
with the [.sup.18 F]fluoride ion in sterile water, to a suitable
reaction vessel having a sufficient amount, such as 60 to 95 volume
%, of an organic solvent based on the total volume of mixture.
Inert organic solvents which can be used are for example
acetonitrile, and propionitrile. The resulting mixture can then be
concentrated at a pressure in the range of from 0.5 to 5 torr under
an inert atmosphere such as helium, along with vigorous stirring
with the flask in an oil bath set at 40.degree. C. to 80.degree. C.
If desired, after the first concentration, a second aliquot of
organic solvent can be added and the concentration repeated. The
1,3,4,6-tetra-O-acetyl-2-triflate-.beta.-D-mannopyranose, referred
to hereinafter as "triflate", can be added to the resulting mixture
as an organic solvent solution. The resulting mixture can then be
agitated for an additional period such as from 4 to 15 minutes
under inert gas atmosphere with the flask in an oil bath set at
60.degree. C. to 100.degree. C. After evaporation of the organic
solvent in vacuo, an aqueous hydrogen halide solution such as a
solution of HCl having a 1 to 2 normality can be added to the
resulting mixture. The mixture can be heated for an additional
period of time such as from 10 to 25 minutes in an oil bath set at
110.degree. C. to 130.degree. C. under an inert gas atmosphere.
Recovery of the [.sup.18 F]2FDG can be achieved by passing the
reaction mixture through quaternary amine functionalized silica or
ion retardation resin to effect neutralization, a C18 reverse-phase
silica or charcoal can be used to effect decolorization and neutral
alumina can be used to remove unreacted fluoride. If desired, the
tetraethylammonium ion can be removed by first passing the reaction
mixture through sulfonic acid functionalized polystyrene resin or
sulfonic acid functionalized silica; the yield of [.sup.18 F]2FDG
is not affected by this last treatment. Quantification of the
[.sup.18 F]2FDG can be done with TLC coupled with BioScan analysis
of the TLC plate and total radioactivity measurement of the sample
with a Capintec detector.
In order that those skilled in the art will be better able to
practice the present invention, the following examples are given by
way of illustration and not by way of limitation. All parts are by
weight unless otherwise indicated.
EXAMPLE 1
Tetraethylammonium bicarbonate was prepared as follows:
40 ml of a 25% w/v solution of tetraethylammonium hydroxide (Kodak)
was treated with 80 ml of water. The pH of this mixture (1 ml
treated with 9 ml of water) was 12.7. The solution was treated with
CO.sub.2 until the pH had stabilized at 7.6. The reaction mixture
was concentrated, taken up in acetonitrile (175 ml) and filtered to
yield a solution of tetraethylammonium bicarbonate ready for
use.
After bombardment, water enriched with H.sub.2.sup.18 O, was
recovered by distillation of the contents in a cyclotron target
cell. The residue in the distillation pot (which Contained the
.sup.18 F) was taken up in sterile water and used as is. Enough of
this aqueous solution of [.sup.18 F]fluoride to provide 10-20 mCi
of activity (anywhere from 100 to 1000 .mu.l) was added to a
borosilicate flask containing 50 .mu.mol of tetraethylammonium
bicarbonate as an acetonitrile solution along with 4 additional ml
of acetonitrile. The mixture was concentrated under reduced
pressure (1 torr) using a nitrogen bleed with the flask in an oil
bath set at 65.degree. C. An additional 5 mL of acetonitrile was
then added to the mixture which was further concentrated. There was
added to the mixture 40 mg (83.3 .mu.mol) of triflate and 4 mL of
acetonitrile. The mixture was stirred for 8 minutes under helium at
a temperature of 100.degree. C. The reaction mixture was
concentrated and 2 mL of 2N HCl was added. The mixture under a
nitrogen atmosphere, was heated for 20 minutes in an oil bath set
at 125.degree. C. The mixture was than passed through an ion
retardation column (BioRad Econo-Pac Ion Retardation column
prefilled with AG 11-A8) to effect neutralization, a C18 reverse
phase sep-pak (Waters) to effect decolorization and a neutral
alumina sep-pak (Waters) to remove fluoride. The [.sup.18 F]2FDG
was quantitated using thin layer chromatography on a silica support
and, independently on a C18 reverse phase support coupled with
BioScan analysis of the TLC plates and measurement of the total
radioactivity in the sample with a Capintec monitor. The above
procedure was repeated except that in place of the
tetraethylammonium bicarbonate phasetransfer reagent, there was
used tetraethylammonium hydroxide and tetrabutylammonium
bicarbonate. In addition a comparative run was also made with
Kryptofix 222-K.sub.2 CO.sub.3 as the phase-transfer reagent, in
accordance with the teaching of K. Hamacher et al, Journal Nuclear
Medicine 27:235-238 (1986) except that the intermediate clean-up
procedure to remove Kryptofix 222 was replaced with a sulfonic acid
functionalized polystyrene resin (Dowex 50X, H= form, 50-100 mesh)
at the end of the synthesis. The following results were
obtained:
______________________________________ Yields of [.sup.18 F]2FDG
PTR EOB [.sup.18 F]2FDG Reagent (.mu.mol) Yield Std Dev n
______________________________________ TEAOH 68 4% 1 TEAHCO.sub.3
51 48% 9% 3 TBAHCO.sub.3 43 63% 9% 3 Kryptofix 222-K.sub.2 CO.sub.3
67 57% 14% 4 ______________________________________ where n is the
number of runs
The above results show that tetraalkyl bicarbonates of the present
invention (TEAHCO.sub.3 and TBAHCO.sub.3) provide significantly
better yields than the corresponding tetraethylammonium hydroxide
when employed as a phase-transfer reagent in the synthesis of
[.sup.18 F]2FDG. It was further found that when the
tetraalkylammonium bicarbonates were used as phase-transfer
reagents, in the synthesis of .sup.19 F]2FDG, that
tetraethylammonium bicarbonate provided a yield of 41%,
tetrabutylammonium bicarbonate provided a yield of 63% and
tetrahexylammonium bicarbonate provided a yield of 59%. It was also
found that when tetraethylammonium hydroxide was used in
combination with potassium bicarbonate at substantially equal molar
amounts as the phase-transfer catalyst, a yield of 34% was
obtained. However, when tetraethylammonium carbonate was used as a
phase-transfer reagent following the same procedure, a yield of
only 20% of the [.sup.19 F]2FDG was obtained. In addition,
tetraethylammonium hydroxide provided a yield of only 5% while
Kryptofix 222-K.sub.2 CO.sub.3 provided a yield of 44% of the
[.sup.19 F]2FDG. These results further confirm the unexpected
advantages achieved by employing tetraalkyl bicarbonate
phase-transfer reagents in accordance with the present
invention.
Although the above example is directed to only a few of the very
many variables which can be employed in the practice of the present
invention, it should be understood that additional conditions and
reagents can be used in the practice of the present invention as
set forth in the description preceding this example.
* * * * *